Abstract As the population ages, late-onset Alzheimer's disease (AD) is becoming an increasingly important public health issue. Clinical trials targeted at reducing AD progression have demonstrated that patients continue to decline despite therapeutic intervention. Thus, there is a pressing need for new treatments aimed at novel therapeutic targets. A shift in focus from risk to resilience has tremendous potential to have a major public health impact by highlighting mechanisms that naturally counteract the damaging effects of AD neuropathology. Interestingly, at autopsy, approximately 30% of cognitively normal individuals have the pathological features of AD. Research from both our group and others has begun to uncover genetic factors that explain some of the observed disconnect between neuropathology and clinical dementia. However, small sample sizes have limited advances in characterizing the heritability and genetic architecture of resilience in a comprehensive manner. Therefore, this project will perform a large, comprehensive analysis of genetic resilience by integrating in vivo biomarker and autopsy data into a unified model of resilience. We propose to leverage a Vanderbilt resource called the Resilience from Alzheimer's Disease (RAD) database to uncover novel protective genetic effects. In RAD, we have developed and validated continuous metrics of resilience that quantify the degree to which an individual is resilient to both the cognitive deficits and the neurodegeneration associated with AD neuropathology. Our strong interdisciplinary team is uniquely positioned to characterize the genetic architecture of resilience leveraging the infrastructure and rich data resources of the AD genetic consortium and the AD sequencing project. We will identify and replicate common and rare genetic variants that predict protection from cognitive impairment and protection from neurodegeneration. Additionally, we will integrate known sex differences in the downstream consequences of AD neuropathology to identify sex- specific genes and pathways that promote resilience. The genes and pathways identified will offer novel therapeutic targets for intervention aimed at activating compensatory mechanisms that confer resilience to the damaging effects of AD neuropathology.